One of the most significant findings that has emerged from the studies performed in our laboratory over the last few years was that ER is a bona fide drug discovery target in tamoxifen-refractory ER-positive breast tumors. Building on this observation, we propose to explore the feasibility of developing drugs that inhibit ER-action in a manner distinct from known antiestrogens. All of the currently available antiestrogens function by (a) binding to the ER ligand binding pocket thereby competitively blocking agonist access and (b) inducing a conformational change within the receptor that prevents it from interacting efficiently with transcription coactivators (i.e. SRC-1, AIB-1 and GRIP-i). In the Current proposal, a strategy is outlined that will enable the development of a novel class of ER-antagonists that function by directly blocking the ability of ER to interact with transcription coactivators within target cells. This objective will be accomplished using combinatorial phage display technology to identify small peptides that interact directly with the two known estrogen receptors, ERa and/or ERB, in the presence of 17-B-estradiol and prevent them from coupling with required coactivators. In a preliminary study, designed to test the feasibility of this approach, we were able to isolate a series of peptides that interacted with and inhibited ERa and/or ERB-mediated transcriptional activity in transfected mammalian cells. Based on these data, we anticipate that it will be possible to develop these peptides, or peptidomimetic derivatives, into pharmaceuticals for use as breast cancer chemotherapeutics. It is likely that drugs of this type could be used in combination with classical antiestrogens, such as tamoxifen, to achieve a complete blockage of ER-signaling. Although ER is the focus of our current studies, we expect that the insights gained from the studies proposed will apply to other nuclear receptors and transcription factors. In particular, we see that this approach would be applicable to the treatment of anti-androgen resistant prostate cancers where receptor mutations enable the inappropriate recruitment of transcription coactivators.